281 ‒ Longevity drugs, aging biomarkers, and updated findings from the Interventions Testing Program

KEYPOINTS

• 01

  The ITP is a small, rigorous program for testing longevity drugs in mice.

  Miller, who directs aging research at the University of Michigan, describes the NIA-funded Interventions Testing Program. It runs at three sites: Michigan, UT San Antonio (Randy Strong) and the Jackson Laboratory. Each gets about $1 million a year in direct costs, roughly $4.5 million in total. Anyone can nominate a compound; there were 28 nominations in a record year, and about six are chosen annually. About 100 drugs have been tested in 20 years. Miller says the budget is not too small.

• 02

  Genetically diverse mice are essential; the standard inbred B6 mouse misleads.

  About 97% of aged-mouse requests are for one inbred strain, C57BL/6. Every B6 mouse is identical and inbred, many are deaf by a year old, and drug effects often don't carry over to other strains. Miller compares it to testing a cancer drug on identical triplets. The ITP uses UM-HET3 mice, which share four grandparent strains, so the population is reproducible but every animal is different. About 12,000 DNA samples from mice with known lifespans have also allowed lifespan genes to be mapped.

• 03

  Study design is pre-specified and statistically conservative.

  The primary endpoint is overall death risk, roughly equivalent to median lifespan. For maximum lifespan they use the Wang–Allison test: what share of the mice still alive at the pooled 90th percentile were treated? Each year has 300 male and 300 female controls and 150 of each sex per drug. That gives 80% power to detect about a 12% effect even if one site failed. Michigan males consistently live 5–10% longer than at other sites, for unknown reasons, so results are analysed site by site and then pooled. Drug levels in food and tissue are confirmed first. Rapamycin needed encapsulation because stomach acid destroyed about 90% of it.

• 04

  Four drugs give more than a 10% lifespan gain, compared with about 3% for curing cancer.

  Work by Jay Olshansky and Bruce Carnes (1990) estimated that eliminating cancer or heart attacks after 50 would raise human median lifespan less than 3%. The ITP's winners are rapamycin, acarbose, 17α-estradiol and canagliflozin. Rapamycin plus acarbose gave a 29% increase in males, the largest yet and the first gain from a combination. Rapamycin consistently benefits females more, possibly because their blood levels are about three times higher. Canagliflozin works only in males, and in aging females blood levels reach about 10 times those of young males, likely toxic.

• 05

  Starting late still works.

  Rapamycin started at 20 months (roughly a 55–60-year-old human) extended lifespan as much as starting young, in both sexes. 17α-estradiol and canagliflozin work in middle-aged males. Acarbose works about half as well when started late. Mice given acarbose or 17α-estradiol in middle age also had better grip strength and rotarod performance. Rapamycin, originally nominated by Dave Sharp based on mTOR genetics in worms and flies, also boosted vaccine responses in old mice.

• 06

  17α-estradiol is a male-only puzzle.

  It's a stereoisomer that barely binds classic estrogen receptors. The original idea was to give males estrogen's benefits without feminization. But males ended up outliving females, and females gain nothing. Treated males produced over 20-fold more estriol, but only if not castrated. In unpublished data, 16-hydroxyestriol seems to work in males at least as well, but it's the first drug found to shorten female lifespan.

• 07

  'Aging rate indicators' act like a speedometer rather than an odometer.

  Miller doesn't think we have good biomarkers of biological age. Instead, his lab found 13 traits that shift the same way in 10 slow-aging mouse models (four mutants, calorie restriction, four drugs and a PTEN overexpressor), even in young adults. Examples include more UCP1 in all three fat depots, fewer inflammatory M1 and more M2 macrophages in fat, higher BDNF and doublecortin in the brain, more of the muscle protein FNDC5 and blood irisin, and higher GPLD1 (an exercise-linked factor tied to cognition). For the male-only drugs, these changes appear only in males. Ames dwarf mice given growth hormone for just six weeks as babies lost both their long life and these traits permanently.

• 08

  RNA levels predict protein changes poorly.

  Gary Churchill's Jackson Lab work found only about 30% of age-related protein changes matched mRNA changes. GPLD1 is regulated by cap-independent translation, not transcription. Selective protein breakdown (chaperone-mediated autophagy) also shapes the proteome. Miller says transcript-only studies are 'not only incomplete but mostly wrong.'

• 09

  Notable failures: resveratrol, metformin, nicotinamide riboside and fisetin.

  The NIA director required them to test resveratrol, and it failed at doses David Sinclair recommended. Miller says the positive study used mice on a 60% coconut-oil diet, and experts' suggested doses spanned a million-fold range. Metformin failed, and others confirmed it. NR failed alone but will be tried in combination, and Miller keeps an open mind about NAD. Fisetin, suggested by Jim Kirkland and Paul Robbins, didn't extend life and didn't reduce p16, p21 or β-gal markers in blinded tissue analyses.